Accelerated growth rates of recurrent hepatocellular carcinoma after liver transplantation

The growth rates of recurrent hepatocellular carcinoma (HCC) after orthotopic liver transplantation (OLTX) were estimated by calculating the tumor doubling time (TDT) in 20 patients. The mean TDT, calculated by multiple measurement of tumor size, was 44.3 ± 11.3 days (mean ± standard error) in 12 patients with pulmonary metastasis (range, 10 to 161 days) and 37.6 ± 8.9 days (range, 7 to 65 days) in 5 patients with liver allograft recurrence. The TDT as estimated by serum alpha‐fetoprotein (AFP) levels in 6 patients was 37.3 ± 10.0 days (range, 12 to 84 days). The mean TDT obtained from 5 control subjects with HCC who were treated with liver resection (without immunosuppression) was 273.8 ± 79.1 days (range, 82 to 560 days). The disease‐free period and survival time after OLTX both correlated well with the TDT (r = 0.546 and r = 0.701, respectively). The patients with fibrolamellar HCC had a greater TDT and a longer survival time than those with nonfibrolamellar HCC. Despite a wide range of TDT in patients who received transplants, their recurrent HCC tumors grew significantly faster than those of patients with the same disease who did not receive transplants. The factors involved in this accelerated growth rate may include the use of immunosuppressive drugs and the consequent suppression of host immunity against the growth of micrometastasis. Cancer 68:2095–2100. Copyright © 1991 American Cancer Societ

COL4A1 and COL4A2 Mutations Analyses with Perinatal Arterial ?schemic Stroke

Perinatal arterial ischemic stroke (PAIS) is one of the frequent causes of mortality and morbidity, but its etiology remains unclear. COL4A1 and COL4A2 mutations are monogenetic causes of weakness of the basement vascular membranes resulting in cerebral small-vessel disease, cerebral hemorrhage, and porencephaly. We hypothesized that variations in the COL4A1 and COL4A2 genes cause PAIS and performed mutation screening of these genes in 17 PAIS patients by whole-exome sequencing. Clinical, demographic, and laboratory data of the 17 PAIS patients were obtained by evaluating hospital files retrospectively. Patients included in the study were invited to the clinic for COL4A1 and COL4A2 mutation analysis. Results: The patient group consisted of 13 females (76.5%) and four males (23.5%) with a mean age of 107.4 ± 11.5 months. Maternal/fetal and prothrombotic risk factors identified in 52.9% and 94.1% of the patients, respectively. Whole-exome sequencing analysis did not reveal COL4A1 and COL4A2 pathological mutations in any of the patients.  Although we did not find an association between PAIS and COL4A1 and COL4A2 variations, we believe that new studies with larger patient populations may reveal such a relationship

Late-onset spastic ataxia phenotype in a patient with a homozygous DDHD2 mutation

Autosomal recessive cerebellar ataxias and autosomal recessive hereditary spastic paraplegias (ARHSPs) are clinically and genetically heterogeneous neurological disorders. Herein we describe Japanese siblings with a midlife-onset, slowly progressive type of cerebellar ataxia and spastic paraplegia, without intellectual disability. Using whole exome sequencing, we identified a homozygous missense mutation in DDHD2, whose mutations were recently identified as the cause of early-onset ARHSP with intellectual disability. Brain MRI of the patient showed a thin corpus callosum. Cerebral proton magnetic resonance spectroscopy revealed an abnormal lipid peak in the basal ganglia, which has been reported as the hallmark of DDHD2-related ARHSP (SPG 54). The mutation caused a marked reduction of phospholipase A(1) activity, supporting that this mutation is the cause of SPG54. Our cases indicate that the possibility of SPG54 should also be considered when patients show a combination of adult-onset spastic ataxia and a thin corpus callosum. Magnetic resonance spectroscopy may be helpful in the differential diagnosis of patients with spastic ataxia phenotype.ArticleSCIENTIFIC REPORTS. 4:7132 (2014)journal articl

Exome Sequencing Reveals a Homozygous SYT14 Mutation in Adult-Onset, Autosomal-Recessive Spinocerebellar Ataxia with Psychomotor Retardation

Autosomal-recessive cerebellar ataxias (ARCAs) are clinically and genetically heterogeneous disorders associated with diverse neurological and nonneurological features that occur before the age of 20. Currently, mutations in more than 20 genes have been identified, but approximately half of the ARCA patients remain genetically unresolved. In this report, we describe a Japanese family in which two siblings have slow progression of a type of ARCA with psychomotor retardation. Using whole-exome sequencing combined with homozygosity mapping, we identified a homozygous missense mutation in SYT14, encoding synaptotagmin XIV (SYT14). Expression analysis of the mRNA of SYT14 by a TaqMan assay confirmed that SYT14 mRNA was highly expressed in human fetal and adult brain tissue as well as in the mouse brain (especially in the cerebellum). In an in vitro overexpression system, the mutant SYT14 showed intracellular localization different from that of the wild-type. An immunohistochemical analysis clearly showed that SYT14 is specifically localized to Purkinje cells of the cerebellum in humans and mice. Synaptotagmins are associated with exocytosis of secretory vesicles (including synaptic vesicles), indicating that the alteration of the membrane-trafficking machinery by the SYT14 mutation may represent a distinct pathomechanism associated with human neurodegenerative disorders

Insights into molecular mechanisms of disease in Neurodegeneration with Brain Iron Accumulation; unifying theories.

Neurodegeneration with brain iron accumulation (NBIA) is a group of disorders characterised by dystonia, parkinsonism and spasticity. Iron accumulates in the basal ganglia and may be accompanied by Lewy bodies, axonal swellings and hyperphosphorylated tau depending on NBIA subtype. Mutations in 10 genes have been associated with NBIA that include Ceruloplasmin (Cp) and Ferritin Light Chain (FTL), both directly involved in iron homeostasis, as well as Pantothenate Kinase 2 (PANK2), Phospholipase A2 group 6 (PLA2G6), Fatty acid hydroxylase 2 (FA2H), Coenzyme A synthase (COASY), C19orf12, WDR45 and DCAF17 (C2orf37). These genes are involved in seemingly unrelated cellular pathways, such as lipid metabolism, Coenzyme A synthesis and autophagy. A greater understanding of the cellular pathways that link these genes and the disease mechanisms leading to iron dyshomeostasis is needed. Additionally, the major overlap seen between NBIA and more common neurodegenerative diseases may highlight conserved disease processes. In this review, we will discuss clinical and pathological findings for each NBIA-related gene, discuss proposed disease mechanisms such as mitochondrial health, oxidative damage, autophagy/mitophagy and iron homeostasis and speculate potential overlap between NBIA subtypes

Parthenogenetic mosaicism: generation via second polar body retention and unmasking of a likely causative PER2 variant for hypersomnia

Background Parthenogenetic mosaicism is an extremely rare condition identified only in five subjects to date. The previous studies indicate that this condition is mediated by parthenogenetic activation and is free from a specific phenotype ascribed to unmaking of a maternally inherited recessive variant in the parthenogenetic cell lineage. Results We examined a 28-year-old Japanese 46,XX female with Silver-Russell syndrome and idiopathic hypersomnia. The results revealed (1) predominance of maternally derived alleles for all the differentially methylated regions examined; (2) no disease-related copy-number variant; (3) two types of regions for all chromosomes, i.e., four BAF (B-allele frequency) band regions with single major microsatellite peaks of maternal origin and single minor microsatellite peaks of non-maternal (paternal) origin, and six BAF band regions with single major microsatellite peaks of maternal origin and two minor microsatellite peaks of maternal and non-maternal (paternal) origin; (4) an unmasked extremely rare PER2 variant (c.1403G>A:p.(Arg468Gln)) with high predicted pathogenicity; (5) mildly affected local structure with altered hydrogen bonds of the p.Arg468Gln-PER2 protein; and (6) nucleus-dominant subcellular distribution of the p.Arg468Gln-PER2 protein. Conclusions The above findings imply that the second polar body retention occurred around fertilization, resulting in the generation of the parthenogenetic cell lineage by endoreplication of a female pronucleus and the normal cell lineage by fusion of male and female pronuclei, and that the homozygous PER2 variant in the parthenogenetic cells is the likely causative factor for idiopathic hypersomnia

The impact of world heritage site designation on local communities - A case study of Ogimachi, Shirakawa-mura, Japan

The paper examines economic, socio-cultural, physical and attitudinal changes in/around World Heritage Site (WHS) Ogimachi since WHS designation from the local communities' standpoint and explores the background of these changes and views. Both positive and negative changes for local communities in/around WHS Ogimachi after WHS listing are identified. There are three main factors behind these changes: the extensive and rapid tourism development after WHS inscription; the high level of appeal of a WHS status for domestic tourists; and local people's attitudes towards conservation of the cultural environment and WHS status. In addition to its conservation plan, WHS Ogimachi must have a comprehensive tourism management plan for its successful future as a place to live, as a WHS and a tourist destination

De Novo Mutations in GNAO1, Encoding a Gαo Subunit of Heterotrimeric G Proteins, Cause Epileptic Encephalopathy

Heterotrimeric G proteins, composed of α, β, and γ subunits, can transduce a variety of signals from seven-transmembrane-type receptors to intracellular effectors. By whole-exome sequencing and subsequent mutation screening, we identified de novo heterozygous mutations in GNAO1, which encodes a Gαo subunit of heterotrimeric G proteins, in four individuals with epileptic encephalopathy. Two of the affected individuals also showed involuntary movements. Somatic mosaicism (approximately 35% to 50% of cells, distributed across multiple cell types, harbored the mutation) was shown in one individual. By mapping the mutation onto three-dimensional models of the Gα subunit in three different complexed states, we found that the three mutants (c.521A>G [p.Asp174Gly], c.836T>A [p.Ile279Asn], and c.572_592del [p.Thr191_Phe197del]) are predicted to destabilize the Gα subunit fold. A fourth mutant (c.607G>A), in which the Gly203 residue located within the highly conserved switch II region is substituted to Arg, is predicted to impair GTP binding and/or activation of downstream effectors, although the p.Gly203Arg substitution might not interfere with Gα binding to G-protein-coupled receptors. Transient-expression experiments suggested that localization to the plasma membrane was variably impaired in the three putatively destabilized mutants. Electrophysiological analysis showed that Gαo-mediated inhibition of calcium currents by norepinephrine tended to be lower in three of the four Gαo mutants. These data suggest that aberrant Gαo signaling can cause multiple neurodevelopmental phenotypes, including epileptic encephalopathy and involuntary movements